An Enzyme‐Cleavable Solubilizing‐Tag Facilitates the Chemical Synthesis of Mirror‐Image Proteins

Author:

Zheng Yupeng12,Zhang Baochang12,Shi Wei‐Wei2,Deng Xiangyu2,Wang Tong‐Yue2,Han Dongyang2,Ren Yuxiang2,Yang Ziyi2,Zhou Yong‐Kang3,Kuang Jian4,Wang Zhi‐Wen4,Tang Shan3,Zheng Ji‐Shen1ORCID

Affiliation:

1. Department of Hematology The First Affiliated Hospital of University of Science and Technology of China (USTC) MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics and Division of Life Sciences and Medicine Hefei National Research Center for Interdisciplinary Sciences at the Microscale University of Science and Technology of China Hefei Anhui 230001 China

2. Department of Chemistry Tsinghua University Beijing 100084 China

3. Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230027 China

4. Department of Chemistry University of Science and Technology of China Hefei Anhui 230026 China

Abstract

AbstractMirror‐image proteins (D‐proteins) are useful in biomedical research for purposes such as mirror‐image screening for D‐peptide drug discovery, but the chemical synthesis of many D‐proteins is often low yielding due to the poor solubility or aggregation of their constituent peptide segments. Here, we report a Lys‐C protease‐cleavable solubilizing tag and its use to synthesize difficult‐to‐obtain D‐proteins. Our tag is easily installed onto multiple amino acids such as DLys, DSer, DThr, and/or the N‐terminal amino acid of hydrophobic D‐peptides, is impervious to various reaction conditions, such as peptide synthesis, ligation, desulfurization, and transition metal‐mediated deprotection, and yet can be completely removed by Lys‐C protease under denaturing conditions to give the desired D‐protein. The efficacy and practicality of the new method were exemplified in the synthesis of two challenging D‐proteins: D‐enantiomers of programmed cell death protein 1 IgV domain and SARS‐CoV‐2 envelope protein, in high yield. This work demonstrates that the enzymatic cleavage of solubilizing tags under denaturing conditions is feasible, thus paving the way for the production of more D‐proteins.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Collaborative Innovation Center for Water Treatment Technology and Materials

National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of Sciences

Publisher

Wiley

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